Substituted aryl or heteroarylamides having retinoid-like biological activity

ABSTRACT

Compounds of the formula  
                 
 
     wherein X is CH or N; R 1  is independently H or alkyl of 1 to 6 carbons; m is an integer having the value of 0-5; p is an integer having the value of 0-2; r is an integer having the value 0-2; L is —(C═Z)—NH— or —NH—(C═Z)— where Z is 0 or S; Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionally substituted with one or two R 1  groups; W is a substituent selected from the group consisting of F, Br, Cl, I, C 1-6 alkyl, fluoro substituted C 1-6  alkyl, NO 2 , N 3 , OH, OCH 2 OCH 3 , OC 1-10 alkyl, tetrazol, CN, SO 2 C 1-6 -alkyl, SO 2 C 1-6 -alkyl, SO 2 C 1-6 -fluoro substituted alkyl, SO—C 1-6  alkyl, CO—C 1-6 alkyl, COOR 8 , phenyl, phenyl itself substituted with a W group other than with phenyl or substituted phenyl with the proviso that when X is CH and r is 0 then p is not 0 and at least one W group is not alkyl; A is (CH 2 ) q  where q is 0-5, lower branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and B is COOH or a pharmaceutically acceptable salt thereof, COOR 8 , CONR 9 R 10 , —CH 2 OH, CH 2 OR 11 , CH 2 OCOR 11 , CHO, CH(OR 12 ) 2 , CHOR 13 O, —COR 7 , CR 7 (OR 12 ) 2 , CR 7 OR 13 O, where R 7  is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R 8  is an alkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R 8  is phenyl or lower alkylphenyl, R 9  and R 10  independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R 11  is lower alkyl, phenyl or lower alkylphenyl, R 12  is lower alkyl, and R 13  is divalent alkyl radical of 2-5 carbons, have retinoid-like biological activity.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to novel compounds havingretinoid-like biological activity. More specifically, the presentinvention relates to amides formed between aryl or heteraryl amines andaryl or heteroaryl carboxylic acids where one of the aromatic orheteroaromatic moieties bears an electron withdrawing substituent. Thecompounds have retinoid-like biological activity.

[0003] 2. Background Art

[0004] Compounds which have retinoid-like activity are well known in theart, and are described in numerous United States and other patents andin scientific publications. It is generally known and accepted in theart that retinoid-like activity is useful for treating animals of themammalian species, including humans, for curing or alleviating thesymptoms and conditions of numerous diseases and conditions. In otherwords, it is generally accepted in the art that pharmaceuticalcompositions having a retinoid-like compound or compounds as the activeingredient are useful as regulators of cell proliferation anddifferentiation, and particularly as agents for treating skin-relateddiseases, including, actinic keratoses, arsenic keratoses, inflammatoryand non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. Retinoidcompounds are also useful for the prevention and treatment of cancerousand precancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition,retinoid compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for retinoid compounds include the prevention and treatmentof conditions and diseases associated with human papilloma virus (HPV),including warts and genital warts, various inflammatory diseases such aspulmonary fibrosis, ileitis, colitis and Krohn's disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and stroke, improper pituitary function, including insufficientproduction of growth hormone, modulation of apoptosis, including boththe induction of apoptosis and inhibition of T-Cell activated apoptosis,restoration of hair growth, including combination therapies with thepresent compounds and other agents such as Minoxidil®, diseasesassociated with the immune system, including use of the presentcompounds as immunosuppressants and immunostimulants, modulation oforgan transplant rejection and facilitation of wound healing, includingmodulation of chelosis.

[0005] U.S. Pat. No. 4,723,028 (Shudo), Published European PatentApplication Nos. 0 170 105 (Shudo), German Patent Application No. DE3524199 A1 (Shudo), PCT WO 91/16051 (Spada et al.), PCT WO 85/04652(Polus) and J. Med Chem. 1988 31, 2182-2192 (Kaqechika et al.), describeor relate to aryl and heteroary or diary substituted olephines or amideshaving retinoid-like or related biological activity.

[0006] U.S. Pat. Nos. 4,992,468, 5,013,744, 5,068,252, 5,175,185,5,202,471, 5,264,456, 5,324,840, 5,326,898, 5,349,105, 5,391,753,5,414,007 and 5,434,173 (assigned to the same assignee as the presentapplication) and patents and publications cited therein, describe orrelate to compounds which have retinoid-like biological activity and astructure wherein a phenyl and a heteroaryl or a phenyl and a secondphenyl group is linked with an olephinic or acetylenic linkage. Stillfurther, several co-pending applications and recently issued patentswhich are assigned to the assignee of the present application, aredirected to further compounds having retinoid-like activity.

[0007] It is now general knowledge in the art that two main types ofretinoid receptors exist in mammals (and other organisms). The two maintypes or families of receptors are respectively designated RARs andRXRs. Within each type there are subtypes; in the RAR family thesubtypes are designated RAR_(α), RAR_(β) and RAR_(Γ), in RXR thesubtypes are: RXR_(α), RXB_(β) and RXR_(Γ). It has also been establishedin the art that the distribution of the two main retinoid receptortypes, and of the several sub-types is not uniform in the varioustissues and organs of mammalian organisms. Accordingly, among compoundscapable of binding to retinoid receptors, specificity or selectivity forone of the main types or families, and even specificity or selectivityfor one or more subtypes within a family of receptors, is considered adesirable pharmacological property.

[0008] The present invention provides compounds having retinoid-likebiological activity and specifically compounds which bind to one or moreRAR retinoid receptor subtypes.

SUMMARY OF THE INVENTION

[0009] The present invention covers compounds of Formula

[0010] wherein X is CH or N;

[0011] R₁ is independently H or alkyl of 1 to 6 carbons;

[0012] m is an integer having the value of 0-5;

[0013] p is an integer having the value of 0-2;

[0014] r is an integer having the value 0-2;

[0015] L is —(C═Z)—NH— or —NH—(C═Z)— where Z is 0 or S;

[0016] Y is a phenyl or naphthyl group, or heteroaryl selected from agroup consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl,naphthyl and heteroaryl groups being optionally substituted with one ortwo R₁ groups;

[0017] W is a substituent selected from the group consisting of F, Br,Cl, I, C₁₋₆alkyl, fluoro substituted C₁₋₆ alkyl, NO₂, N₃, OH, OCH₂OCH₃,OC₁₋₁₀alkyl, tetrazol, CN, SO₂C₁₋₆-alkyl, SO₂C₁₋₆-alkyl, SO₂C₁₋₆-fluorosubstituted alkyl, SO—C₁₋₆ alkyl, CO—C₁₋₆alkyl, COOR₈, phenyl, phenylitself substituted with a W group other than with phenyl or substitutedphenyl with the proviso that when X is CH and r is 0 then p is not 0 andat least one W group is not alkyl;

[0018] A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds, and

[0019] B is COOH or a pharmaceutically acceptable salt thereof, COOR₈,CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O, —COR₇,CR₇(OR₁₂)₂, CR₇OR₁₃O, where R₇ is an alkyl, cycloalkyl or alkenyl groupcontaining 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons.

[0020] In a second aspect, this invention relates to the use of thecompounds of Formula 1 for the treatment of skin-related diseases,including, without limitation, actinic keratoses, arsenic keratoses,inflammatory and non-inflammatory acne, psoriasis, ichthyoses and otherkeratinization and hyperproliferative disorders of the skin, eczema,atopic dermatitis, Darriers disease, lichen planus, prevention andreversal of glucocorticoid damage (steroid atrophy), as a topicalanti-microbial, as skin anti-pigmentation agents and to treat andreverse the effects of age and photo damage to the skin. The compoundsare also useful for the prevention and treatment of cancerous andprecancerous conditions, including, premalignant and malignanthyperproliferative diseases such as cancers of the breast, skin,prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung,larynx, oral cavity, blood and lymphatic system, metaplasias,dysplasias, neoplasias, leukoplakias and papillomas of the mucousmembranes and in the treatment of Kaposi's sarcoma. In addition, thepresent compounds can be used as agents to treat diseases of the eye,including, without limitation, proliferative vitreoretinopathy (PVR),retinal detachment, dry eye and other corneopathies, as well as in thetreatment and prevention of various cardiovascular diseases, including,without limitation, diseases associated with lipid metabolism such asdyslipidemias, prevention of post-angioplasty restenosis and as an agentto increase the level of circulating tissue plasminogen activator (TPA).Other uses for the compounds of the present invention include theprevention and treatment of conditions and diseases associated withhuman papilloma virus (HPV), including warts and genital warts, variousinflammatory diseases such as pulmonary fibrosis, ileitis, colitis andKrohn's disease, neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and stroke, improper pituitary function, includinginsufficient production of growth hormone, modulation of apoptosis,including both the induction of apoptosis and inhibition of T-Cellactivated apoptosis, restoration of hair growth, including combinationtherapies with the present compounds and other agents such asMinoxidil®, diseases associated with the immune system, including use ofthe present compounds as immunosuppressants and immunostimulants,modulation of organ transplant rejection and facilitation of woundhealing, including modulation of chelosis.

[0021] This invention also relates to a pharmaceutical formulationcomprising a compound of Formula 1 in admixture with a pharmaceuticallyacceptable excipient.

[0022] In another aspect, this invention relates to processes for makinga compound of Formula 1 which processes comprise reacting, in thepresence of an acid acceptor or water acceptor, a compound of Formula 2with a compound of Formula 3 where X₁ is OH, halogen, or other groupwhich renders the —COX₁ group reactive for amide formation, and wherethe remaining symbols are defined as in connection with Formula 1.Alternatively, the process of the invention comprises reacting acompound of Formula 2a with a compound of Formula 3a, where the symbolsare defined as above.

[0023] Still further, the present invention relates to such reactionsperformed on the compounds of Formula 1 which cause transformations ofthe B group while the reaction product still remains within the scope ofFormula 1.

General Embodiments

[0024] Definitions

[0025] The term alkyl refers to and covers any and all groups which areknown as normal alkyl, branched-chain alkyl and cycloalkyl. The termalkenyl refers to and covers normal alkenyl, branch chain alkenyl andcycloalkenyl groups having one or more sites of unsaturation. Similarly,the term alkynyl refers to and covers normal alkynyl, and branch chainalkynyl groups having one or more triple bonds.

[0026] Lower alkyl means the above-defined broad definition of alkylgroups having 1 to 6 carbons in case of normal lower alkyl, and asapplicable 3 to 6 carbons for lower branch chained and cycloalkylgroups. Lower alkenyl is defined similarly having 2 to 6 carbons fornormal lower alkenyl groups, and 3 to 6 carbons for branch chained andcyclo- lower alkenyl groups. Lower alkynyl is also defined similarly,having 2 to 6 carbons for normal lower alkynyl groups, and 4 to 6carbons for branch chained lower alkynyl groups.

[0027] The term “ester” as used here refers to and covers any compoundfalling within the definition of that term as classically used inorganic chemistry. It includes organic and inorganic esters. Where B ofFormula 1 is —COOH, this term covers the products derived from treatmentof this function with alcohols or thioalcohols preferably with aliphaticalcohols having 1-6 carbons. Where the ester is derived from compoundswhere B is —CH₂OH, this term covers compounds derived from organic acidscapable of forming esters including phosphorous based and sulfur basedacids, or compounds of the formula —CH₂OCOR₁₁ where R₁₁ is anysubstituted or unsubstituted aliphatic, aromatic, heteroaromatic oraliphatic aromatic group, preferably with 1-6 carbons in the aliphaticportions.

[0028] Unless stated otherwise in this application, preferred esters arederived from the saturated aliphatic alcohols or acids of ten or fewercarbon atoms or the cyclic or saturated aliphatic cyclic alcohols andacids of 5 to 10 carbon atoms. Particularly preferred aliphatic estersare those derived from lower alkyl acids and alcohols. Also preferredare the phenyl or lower alkyl phenyl esters.

[0029] Amides has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono- and di-substituted amides. Unless statedotherwise in this application, preferred amides are the mono- anddi-substituted amides derived from the saturated aliphatic radicals often or fewer carbon atoms or the cyclic or saturated aliphatic-cyclicradicals of 5 to 10 carbon atoms. Particularly preferred amides arethose derived from substituted and unsubstituted lower alkyl amines.Also preferred are mono- and disubstituted amides derived from thesubstituted and unsubstituted phenyl or lower alkylphenyl amines.Unsubstituted amides are also preferred.

[0030] Acetals and ketals include the radicals of the formula-CK where Kis (—OR)₂. Here, R is lower alkyl. Also, K may be —OR₇O— where R₇ islower alkyl of 2-5 carbon atoms, straight chain or branched.

[0031] A pharmaceutically acceptable salt may be prepared for anycompounds in this invention having a functionality capable of formingsuch-salt, for example an acid functionality. A pharmaceuticallyacceptable salt is any salt which retains the activity of the parentcompound and does not impart any deleterious or untoward effect on thesubject to which it is administered and in the context in which it isadministered. Pharmaceutically acceptable salts may be derived fromorganic or inorganic bases. The salt may be a mono or polyvalent ion. Ofparticular interest are the inorganic ions, sodium, potassium, calcium,and magnesium. Organic salts may by be made with amines, particularlyammonium salts such as mono-, di- and trialkyl amines or ethanol amines.Salts may also be formed with caffeine, tromethamine and similarmolecules. Where there is a nitrogen sufficiently basic as to be capableof forming acid addition salts, such may be formed with any inorganic ororganic acids or alkylating agent such as methyl iodide. Preferred saltsare those formed with inorganic acids such as hydrochloric acid,sulfuric acid or phosphoric acid. Any of a number of simple organicacids such as mono-, di- or tri- acid may also be used.

[0032] Some of the compounds of the present invention may have trans andcis (E and Z) isomers. In addition, the compounds of the presentinvention may contain one or more chiral centers and therefore may existin enantiomeric and diastereomeric forms. The scope of the presentinvention is intended to cover all such isomers per se, as well asmixtures of cis and trans isomers, mixtures of diastereomers and racemicmixtures of enantiomers (optical isomers) as well.

[0033] With reference to the symbol X in Formula 1, compounds areequally preferred where X is CH or N. When X is CH then the benzene ringis preferably 1, 3, 5 substituted with the L group occupying the 1position and the W and/or R₁ groups occupying the 3 and 5 positions.When the symbol X is N, then the pyridine ring is preferably 2,4,6substituted with the L group occupying the 4 position and the W and/orR₁ groups occupying the 2 and 6 positions.

[0034] The L group of Formula 1 is preferably —(C═Z)—NH—, and Z ispreferably 0. In other words, those carbamoyl or amide compounds arepreferred in accordance with the present invention where the —NH-moietyis attached to the Y group.

[0035] Referring now to the W group in Formula 1, this group is,generally speaking, an electron withdrawing group. W is present in thecompounds of the invention either in the phenyl or pyridyl ring (shownin Formula 1 as substituent “(W)_(p)”) and/or as a substituent of thearyl or heteroaryl group Y. Preferably, the W group is present in the Ygroup, or both in the Y group and in the phenyl or pyridyl ringdiscussed above. In the aryl or heteroaryl Y moiety the W group ispreferably located in the position adjacent to the A-B group; preferablythe A-B group is in para position in the phenyl ring relative to the L(amide or carbamoyl) moiety, and therefore the W group is preferably inmeta position relative to the L (amide or carbamoyl) moiety. Preferred Wgroups are F, NO₂, Br, I, CF₃, N₃, and OH. Alternatively, in the phenylor pyridyl ring (shown in Formula 1 as substituent “(W)_(p)”) W is analkyl group, preferably branch-chained alkyl, such as tertiary butyl,and preferably p is 2. Moreover, the presence of one or two fluorosubstituents in the Y group is especially preferred. When the Y group isphenyl, the fluoro substituents preferably are in the ortho and ortho′positions relative to the A-B group.

[0036] With reference to the symbol Y in Formula 1, the preferredcompounds of the invention are those where Y is phenyl, pyridyl,2-thiazolyl, thienyl, or furyl, more preferably phenyl. As far assubstitutions on the Y (phenyl) and Y (pyridyl) groups are concerned,compounds are preferred where the phenyl group is 1,4 (para) substitutedby the L and A-B groups, and where the pyridine ring is 2,5 substitutedby the L and A-B groups. (Substitution in the 2,5 positions in the“pyridine” nomenclature corresponds to substitution in the 6-position inthe “nicotinic acid” nomenclature.) In the preferred compounds of theinvention there is no optional R₁ substituent (other than H) on the Ygroup.

[0037] The R₁ groups, when present, preferably are H or CH₃.

[0038] The A-B group of the preferred compounds is (CH₂)_(n)—COOH or(CH₂)_(n)—COOR₈, where n and R₈ are defined as above. Even morepreferably n is zero and R₈ is lower alkyl, or n is zero and B is COOHor a pharmaceutically acceptable salt thereof.

[0039] The most preferred compounds of the invention are shown in Table1, with reference to Formula 4. TABLE 1 Formula 4

Compound # X W₁ W₂ W₃ R₈*  1 N H F H Et  2 N H F H H  3 N H H H Et  4 NH H H H  5 CH H F H Et  6 CH H F H H  7 CH OH F H Et  8 CH OH F H H  9 NH F F Me 10 N H F F H 11 CH H F F Me 12 CH H F F H 13 N H NO₂ H Me 14 NH NO₂ H H 15¹ CH H H H H

Modes of Administration

[0040] The compounds of this invention may be administered systemicallyor topically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and numerous other considerations.

[0041] In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne or psoriasis, oral administration may also beused. Any common topical formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, these compounds could also be administered as a powder orspray, particularly in aerosol form. If the drug is to be administeredsystemically, it may be confected as a powder, pill, tablet or the likeor as a syrup or elixir suitable for oral administration. Forintravenous or intraperitoneal administration, the compound will beprepared as a solution or suspension capable of being administered byinjection. In certain cases, it may be useful to formulate thesecompounds by injection. In certain cases, it may be useful to formulatethese compounds in suppository form or as extended release formulationfor deposit under the skin or intramuscular injection.

[0042] Other medicaments can be added to such topical formulation forsuch secondary purposes as treating skin dryness; providing protectionagainst light; other medications for treating dermatoses; medicamentsfor preventing infection, reducing irritation, inflammation and thelike.

[0043] Treatment of dermatoses or any other indications known ordiscovered to be susceptible to treatment by retinoic acid-likecompounds will be effected by administration of the therapeuticallyeffective dose of one or more compounds of the instant invention. Atherapeutic concentration will be that concentration which effectsreduction of the particular condition, or retards it expansion. Incertain instances, the compound potentially may be used in prophylacticmanner to prevent onset of a particular condition.

[0044] A useful therapeutic or prophylactic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, no single concentration will be uniformlyuseful, but will require modification depending on the particularitiesof the disease being treated. Such concentrations can be arrived atthrough routine experimentation. However, it is anticipated that in thetreatment of, for example, acne, or similar dermatoses, that aformulation containing between 0.01 and 1.0 milligrams per mililiter offormulation will constitute a therapeutically effective concentrationfor total application. If administered systemically, an amount between0.01 and 5 mg per kg per day of body weight would be expected to effecta therapeutic result in the treatment of many disease for which thesecompounds are useful.

Assay of Retinoid-like Biological Activity

[0045] The retinoid-like activity of the compounds of the invention canbe confirmed in assays wherein ability of the compound to bind toretinoid receptors is measured. As it is noted in the introductorysection of this application for patent two main types of retinoic acidreceptors (RAR and RXR) exist in mammals (and other organisms). Withineach type there are sub-types (RAR_(α), RAR_(β), RAR_(Γ), RXR_(α),RXR_(β) and RXR_(Γ)) the distribution of which is not uniform in thevarious tissues and organs of mammalian organisms. Selective binding ofonly one or two retinoid receptor subtypes within one retinoid receptorfamily can give rise to beneficial pharmacological properties because ofthe varying distribution of the sub-types in the several mammaliantissues or organs. For the above-summarized reasons, binding of any orall of the retinoid receptors, as well as specific or selective activityin a receptor family, or selective or specific activity in any one ofthe receptor subtypes, are all considered desirable pharmacologicalproperties.

[0046] In light of the foregoing the prior art has developed assayprocedures for testing the agonist like activity of compounds in theRAR_(α), RAR_(β), RAR_(Γ), RXR_(α), RXR_(β) and RXR_(Γ) receptorsubtypes. For example, a chimeric receptor transactivation assay whichtests for agonist-like activity in the RAR_(α), RAR_(β), RA_(Γ), andRXR_(α) receptor subtypes, and which is based on work published byFeigner P. L. and Holm M. (1989) Focus, 11 2 is described in detail inU.S. Pat. No. 5,455,265. The specification of U.S. Pat. No. 5,455,265 isexpressly incorporated herein by reference.

[0047] A holoreceptor transactivation assay and a ligand binding assaywhich measure the ability of the compounds of the invention to bind tothe several retinoid receptor subtypes, respectively, are described inpublished PCT Application No. WO W093/11755 (particularly on pages 30-33and 37-41) published on Jun. 24, 1993, the specification of which isalso incorporated herein by reference. A description of the ligandbinding assay is also provided below.

[0048] Binding Assay

[0049] All binding assays were performed in a similar fashion. All sixreceptor types were derived from the expressed receptor type (RAR α, β,Γ and RXR α, β, Γ) expressed in Baculovirus. Stock solutions of allcompounds were prepared as 10 mM ethanol solutions and serial dilutionscarried out into 1:1 DMSO; ethanol. Assay buffers consisted of thefollowing for all six receptor assays: 8% glycerol, 120 mM KCl, 8 mMTris, 5 mM CHAPS 4 mM DTT and 0.24 mM PMSF, pH-7.4@room temperature.

[0050] All receptor biding assays were performed in the same manner. Thefinal assay volume was 250 μl and contained from 10-40 μg of extractprotein depending on receptor being assayed along with 5 nM of [³H]all-trans retinoic acid or 10 nM [³H] 9-cis retinoic acid and varyingconcentrations of competing ligand at concentrations that ranged from0-10⁻⁵ M. The assays were formatted for a 96 well minitube system.Incubations were carried out at 4° C. until equilibrium was achieved.Non-specific binding was defined as that binding remaining in thepresence of 1000 nM of the appropriate unlabeled retinoic acid isomer.At the end of the incubation period, 50 μl of 6.25% hydroxyapitite wasadded in the appropriate wash buffer. The wash buffer consisted of 100mM KCl, 10 mM Tris and either 5 mM CHAPS (RXR α, β, Γ) or 0.5% TritonX-100 (RAR α, β, Γ). The mixture was vortexed and incubated for 10minutes at 4° C., centrifuged and the supernatant removed. Thehydroxyapitite was washed three more times with the appropriate washbuffer. The receptor-ligand complex was adsorbed by the hydroxyapitite.The amount of receptor-ligand complex was determined by liquidscintillation counting of hydroxyapitite pellet.

[0051] After correcting for non-specific binding, IC₅₀ values weredetermined. The IC₅₀ value is defined as the concentration of competingligand needed to reduce specific binding by 50%. The IC₅₀ value wasdetermined graphically from a loglogit plot of the data. The K_(d)values were determined by application of the Cheng-Prussof equation tothe IC₅₀ values, the labeled ligand concentration and the K_(d) of thelabeled ligand.

[0052] The results of ligand binding assay are expressed in K_(d)numbers. (See Chena et al. Biochemical Pharmacology Vol. 22 pp3099-3108, expressly incorporated herein by reference.)

[0053] Table 2 shows the results of the ligand binding assay for certainexemplary compounds of the invention. TABLE 2 Ligand Binding Assay K_(d)(nanomolar) Compound # RARα RARβ RARΓ RXRα RXRβ RXRΓ 2 14.00 0.00 0.000.00 0.00 0.00 4 19.00 0.00 0.00 0.00 0.00 0.00 6 26.0 0.00 0.00 0.000.00 0.00 8 77.0 0.00 0.00 0.00 0.00 0.00 10 62.0 0.00 0.00 0.00 0.000.00 12 87.0 0.00 0.00 0.00 0.00 0.00 14 94.0 0.00 0.00 0.00 0.00 0.0015¹ 37.0 0.00 0.00 0.00 0.00 0.00

[0054] As it can be seen from the test results summarized in Table 2,the therein indicated exemplary compounds of the invention bindspecifically or selectively to RARα receptors.

[0055] Cancer Cell Line Assays

[0056] Materials and Methods

[0057] Hormones

[0058] All trans-Retinoic acid (t-RA) (Sigma Chemicals Co., St. Louis,Mo.) was stored at −70° C. Prior to each experiment the compound wasdissolved in 100% ethanol at 1 mM and diluted in culture mediumimmediately before use. All experiments were performed in subdued light.Controls were assayed using the same concentration of ethanol as presentin the experimental plates and this concentration of diluent had noeffect in either assay.

[0059] Cells and Cell Culture

[0060] All cell lines, RPMI 8226, ME-180 and AML-193 were obtained fromthe American Type Culture Collection (ATCC, Rockville, Md.). RPMI 8226is a human hematopoietic cell line obtained from the peripheral blood ofa patient with multiple myeloma. The cells resemble the lymphoblastoidcells of other human lymphocyte cell lines and secrete α-type lightchains of immunoglobulin. RPMI-8226 cells are grown in RPMI medium(Gibco) supplemented with 10% fetal bovine serum, glutamine andantibiotics. The cells were maintained as suspension cultures grown at37° C. in a humidified atmosphere of 5% CO₂ in air. The cells werediluted to a concentration of 1×10⁵/ml twice a week.

[0061] ME-180 is a human epidermoid carcinoma cell line derived from thecervix. The tumor was a highly invasive squamous cell carcinoma withirregular cell clusters and no significant keratinization. ME-180 cellswere grown and maintained in McCoy's 5a medium (Gibco) supplemented with10% fetal bovine serum, glutamine and antibiotics. The cells weremaintained as monolayer cultures grown at 37° C. in a humidifiedatmosphere of 5% CO₂ in air. The cells were diluted to a concentrationof 1×10⁵/ml twice a week.

[0062] AML-193 was established from the blast cells classified as M5Acute Monocyte Leukemia. The growth factor, granulocytecolony-stimulation factor (GM-CSF) as required to establish this cellline and growth factors are necessary for its continuous proliferationin chemically defined medium. AML-193 cells were grown and maintained inIscove's modified Dulbecco's medium supplemented with 10% fetal bovineserum, glutamine and antibiotics with 5 μg/ml insulin (Sigma ChemicalCo.) and 2 ng/ml rh GM-CSF (R and D Systems). The cells were diluted toa concentration of 3×10⁵/ml twice a week.

[0063] Incorporation of ³H-Thymidine

[0064] The method used for determination of the incorporation ofradiolabeled thymidine was adapted from the procedure described byShrivastav et al. RPMI-8226 cells were plated in a 96 well round bottommicrotiter plate (Costar) at a density of 1,000 cells/well. Toappropriate wells, retinoid test compounds were added at the finalconcentrations indicated for a final volume of 150 μl/well. The plateswere incubated for 96 hours at 37° C. in a humidified atmosphere of 5%CO₂ in air. Subsequently, 1 μCi of [5′-³H]-thymidine (Amersham, U.K. 43Ci/mmol specific activity) in 25 μl culture medium was added to eachwell and the cells were incubated for an additional 6 hours. Thecultures were further processed as described below.

[0065] ME-180 wells, harvested by trypsinization were plated in a 96well flat bottom microtiter plate (Costar) at a density of 2,000cells/well. The cultures were treated as described above for RPMI 8226with the following exceptions. After incubation with thymidine thesupernatant was carefully removed, and the cells were washed with a 0.5mM solution of thymidine in phosphate buffered saline. ME180 cells werebriefly treated with 50 μl of 2.5% trypsin to dislodge the cells fromthe plate.

[0066] AML-193 cells were plated in a 96 well round bottom microtiterplate (Costar) at a density of 1,000 cells/well. To appropriate wells,retinoid test compounds were added at the final concentrations indicatedfor a final volume of 150 μl/well. The plates were incubated for 96hours at 37° C. in a humidified atmosphere of 5% CO₂ in air.Subsequently, 1 μCi of [5′-³H]-thymidine (Amersham, U.K., 43 Ci/mmolspecific activity) in 25 μl culture medium was added to each well andthe cells were incubated for an additional 6 hours.

[0067] All cells lines were then processed as follows: the cellular DNAwas precipitated with 10% trichloroacetic acid onto glass fiber filtermats using a SKATRON multi-well cell harvester (Skatron Instruments,Sterling Va.). Radioactivity incorporated into DNA, as a directmeasurement of cell growth, was measured by liquid scintillationcounting. The numbers represent the mean disintegrations per minute ofincorporated thymidine from triplicate wells ±SEM.

[0068] In the above noted in vitro cell lines exemplary Compound 2 ofthe invention caused significant decrease in the proliferation of thetumor cell lines (as measured by incorporation of radioactive labeledthymidine) in the 10⁻¹¹ to 10⁻⁶ molar concentration range of the testcompound.

Specific Embodiments

[0069] The compounds of this invention can be made by the syntheticchemical pathways illustrated here. The synthetic chemist will readilyappreciate that the conditions set out here are specific embodimentswhich can be generalized to any and all of the compounds represented byFormula 1.

[0070] Generally speaking the process of preparing compounds of theinvention involves the formation of an amide by the reaction of acompound of the general Formula 2 with a compound of general Formula 3,or by the reaction of a compound of general Formula 2a with a compoundof general Formula 3a as these formulas are defined in the summarysection of the present application for patent. Thus, as is noted above,a compound of Formula 2 is an acid or an “activated form” of acarboxylic acid attached to a substituted phenyl (in Formula 1 X is CH)or to a substituted pyridyl (in Formula 1 X is N) nucleus.

[0071] The term “activated form” of the carboxylic acid should beunderstood in this regard as such derivative of the carboxylic acidwhich is capable of forming an amide when reacted with a primary amineof Formula 3. In case of the “reverse amides” the activated form of acarboxylic acid is a derivative (Formula 3a) that is capable of formingan amide when reacted with a primary amine of Formula 2a. This,generally speaking, means such derivatives of a carboxylic acid whichare normally known and used in the art to form amide linkages with anamine. Examples of suitable forms or derivatives for this purpose areacid chlorides, acid bromides, and esters of the carboxylic acid,particularly active esters, where the alcohol moiety of the ester formsa good leaving group. Presently most preferred as reagents in accordancewith Formula 2 (or Formula 3a) are acid chlorides (X₁ is Cl). The acidchlorides of Formula 2 (or of Formula 3a) can be prepared by traditionalmethods from the corresponding esters (X₁ is for example ethyl) byhydrolysis and treatment with thionyl chloride (SOCl₂). The acidchlorides of Formula 2 (or of Formula 3a) can also be prepared by directtreatment of the carboxylic acids with thionyl chloride, where thecarboxylic acid, rather than an ester thereof is available commerciallyor by a known synthetic procedure. The acid chlorides of Formula 2 (orof Formula 3a) are typically reacted with the amine of Formula 3 (oramine of Formula 2a) in an inert solvent, such as methylene chloride, inthe presence of an acid acceptor, such as pyridine.

[0072] The carboxylic acids themselves in accordance with Formula 2 (orFormula 3a) are also suitable for amide formation when reacted with anamine, a catalyst (4-dimethylaminopyridine) in the presence of adehydrating agent, such as dicyclohexylcarbodiimide (DCC) or morepereferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC).

[0073] The carboxylic acids or the corresponding esters of Formula 2,are generally speaking, prepared as described in the chemical scientificor patent literature and the literature procedures for their preparationmay be modified, if necessary, by such chemical reactions or processeswhich per se are known in the art. Reaction Scheme 1 provides an examplefor the preparation of 2,6-di-tert-butylisonicotinic acid (Compound C)which is a reagant in accordance with Formula 2 for the preparation ofseveral preferred compounds of the present invention. Thus,2,6-di-tert-butyl-4-methylpyridine (available commercially from AldrichChemical Co.) is reacted with N-bromosuccinimide and benzoyl peroxide toprovide 4-bromomethyl-2,6-di-tert-butylpyridine (Compound A). Compound Ais reacted with base (sodium hydroxyde) to yield the corespondinghydroxymethyl compound (Compound B), which is thereafter oxidized in aJones oxydation reaction to give 2,6-di-tert-butylisonicotinic acid(Compound C).

[0074] A further example of a compound which serves as a reagent forpreparing the carbamoyl (or amide) compounds of the present invention isprovided in Reaction Scheme 1, 2,4-Di-tert-butylphenol (Aldrich) isbrominated in glacial acetic acid to yield2-bromo-4,6-di-tert-butylphenol (Compound D) which is thereafter reactedwith methoxymethyl chloride (MOMCl)to giveO-methoxymethyl-2-bromo-4,6-di-tert-butylphenol (Compound E). Compound Bis treated with t-butyl lithium folowed by carbon dioxide to yieldO-methoxymethyl-3,5-di-tert-butylsalicylic acid (Compound F). Compound Fis a reagent which differs from the compounds generally encompassed byFormula 2 only in that the hydroxyl funtion of this compound isprotected by the methoxymethyl (MOM) group. However, the methoxymethylprotecting group is removed after formation of the carbamoyl (amide)linkage, as exemplified in Reaction Scheme 5. Reaction of an aromaticbromo compound (such as Compound D) with t-butyl lithium followed bycarbon dioxide is a preferred method for preparing several aromaticcarboxylic acids in accordance with Formula 2 and Formula 3a, describedin the present application.

[0075] Reaction Scheme 2 provides examples for the preparation ofaromatic amino carboxylic acids or esters which serve as reagentscorresponding to Formula 3 described above. Thus, in accordance withReaction Scheme 2, 3-nitro-6-methyl-fluorobenzene (Aldrich) is subjectedto oxidation, conversion of the resulting carboxylic acid to an acidchloride and thereafter to an ethyl ester, followed by reduction of thenitro group, to yield ethyl 2-fluoro-4-amino-benzoate (Compound G). Asanother example, 2,4,6-trifluorobenzoic acid (Aldrich) is converted tothe methyl ester through the acid chloride, and the 4-fluoro atom isdisplaced by reaction with sodium azide to give the intermediate azidocompound (Compound H). Compound H is reduced by hydrogenation, to yieldmethyl 2,6-difluoro-4-amino benzoate (Compound I). As still anotherexample, 2-nitro-4-aminobenzoic acid (Research Plus Inc.) is convertedto its methyl ester (Compound K) through the corresponding acidchloride.

[0076] Reaction Scheme 3 illustrates the synthesis of the primary aminecompounds of Formula 2a from the acid chlorides (X₁=Cl) or other form ofactivated acids of Formula 2 where the primary amine of Formula 2a isnot available by a published literature procedure. Thus, substantiallyin accordance with the steps of a Curtius rearrangement, the acidchloride of Formula 2 is reacted with sodium azide in acetone to yieldthe azide compound of Formula 5. The azide of Formula 5 is heated in apolar high boiling solvent, such as t-butanol, to provide theintermediate isocyanate of Formula 6, which is hydrolyzed to yield acompound of Formula 2a.

[0077] Reaction Scheme 4 illustrates examples for preparing compounds ofFormula 3a where such compounds are not available commercially or by apublished literature procedure. Thus, by way of example2,5-difluoro-4-bromobenzoic acid (available by the literature procedureof Sugawara et al. Kogyo Kaguku Zasshi 1970, 73, 972-979, incorporatedherein by reference) is first esterified by treatment with ethyl alcoholand acid to yield the corresponding ester, and thereafter is reactedwith butyl lithium followed by carbon dioxide to give the monoester of2,5-difluoro terephthalic acid (Compound L). A similar sequence ofreactions performed on 2,3,5,6-difluoro-4-bromobenzoic acid (availableby the literature procedure of Reuman et al. J. Med. Chem. 1995, 38,2531-2540, incorporated herein by reference) yields the monoester of2,3,5,6-tetrafluoroterephthalic acid (Compound M) The just illustratedsequence of reactions can be, generally speaking, utilized for thesynthesis of all compounds of Formula 3a with such modification whichwill become readily apparent to those skilled in the art, where suchcompounds are not available by a known literature procedure.

[0078] Numerous other reactions suitable for preparing compounds of theinvention, and for converting compounds of Formula 1 within the scope ofthe present invention into still further compounds of the invention, andalso for preparing the reagents of Formula 2, Formula 3, Formula 2a andFormula 3a will become readily apparent to those skilled in the art inlight of the present disclosure. In this regard the following generalsynthetic methodology, applicable for conversion of the compounds ofFormula 1 into further homologs and/or derivatives, and also forpreparing the reagents of Formula 2 and 3, (as well as 2a and 3a) isnoted.

[0079] Carboxylic acids are typically esterified by refluxing the acidin a solution of the appropriate alcohol in the presence of an acidcatalyst such as hydrogen chloride or thionyl chloride. Alternatively,the carboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, “Advancedorganic Chemistry,” 2nd Edition, McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

[0080] A means for making compounds where A is (CH₂)_(q) (q is 1-5) isto subject the compounds of Formula 1, where B is an acid or otherfunction, to homologation, using the well known Arndt-Eistert method ofhomologation, or other known homologation procedures. Similarhomologations (and several of the other herein mentioned synthetictransformations) can be transformed on the reagents of Formula 3 or 3a.Compounds of the invention, where A is an alkenyl group having one ormore double bonds can be made, for example, by having the requisitenumber of double bonds incorporated into the reagent of Formula 3.Generally speaking, such compounds where A is an unsaturated carbonchain can be obtained by synthetic schemes well known to the practicingorganic chemist; for example by Wittig and like reactions, or byintroduction of a double bond by elimination of halogen from analpha-halo-carboxylic acid, ester or like carboxaldehyde. Compounds ofthe invention where the A group has a triple (acetylenic) bond can bemade by using the corresponding aryl or heteroaryl aldehydeintermediate. Such intermediate can be obtained by reactions well knownin the art, for example, by reaction of a corresponding methyl ketonewith strong base, such as lithium diisopropyl amide.

[0081] The acids and salts derived from compounds of Formula 1 arereadily obtainable from the corresponding esters. Basic saponificationwith an alkali metal base will provide the acid. For example, an esterof Formula 1 may be dissolved in a polar solvent such as an alkanol,preferably under an inert atmosphere at room temperature, with about athree molar excess of base, for example, potassium or lithium hydroxide.The solution is stirred for an extended period of time, between 15 and20 hours, cooled, acidified and the hydrolysate recovered byconventional means.

[0082] The amide (in Formula 1 B is CONR₉R₁₀) may be formed by anyappropriate amidation means known in the art from the correspondingesters or carboxylic acids. One way to prepare such compounds is toconvert an acid to an acid chloride and then treat that compound withammonium hydroxide or an appropriate amine.

[0083] Alcohols are made by converting the corresponding acids to theacid chloride with thionyl chloride or other means (J. March, “AdvancedOrganic Chemistry”, 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alky halides under Williamsonreaction conditions (March, Ibid, pg. 357) gives the correspondingethers. These alcohols can be converted to esters by reacting them withappropriate acids in the presence of acid catalysts ordicyclohexylcarbodiimide and dimethylaminopyridine.

[0084] Aldehydes can be prepared from the corresponding primary alcoholsusing mild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron. 1978, 34, 1651).

[0085] Ketones can be prepared from an appropriate aldehyde by treatingthe aldehyde with an alkyl Grignard reagent or similar reagent followedby oxidation.

[0086] Acetals or ketals can be prepared from the corresponding aldehydeor ketone by the method described in March, Ibid, p 810.

[0087] Compounds of Formula 1 where B is H can be prepared from thecorresponding halogenated aromatic compounds, preferably where thehalogen is I.

[0088] Reaction Scheme 5 illustrates examples for the formation of thecarbamoyl (amide) compounds of the present invention by reaction of areagent of Formula 2 with a reagent of Formula 3. Thus,2,6-di-tert-butylisonicotinic acid (Compound C) is reacted with thionylchloride (SOCl₂) to provide the intermediate acid chloride, which isthen reacted with ethyl 2-fluoro-4-amino-benzoate (Compound G) in thepresence of an acid acceptor (pyridine) to yield ethyl2-fluoro-4-[(2′6′-di-tert-butylpyrid-4′-yl)carbamoyl]benzoate (Compound1). As another example, 3,5-di-tert-butylbenzoic acid (available by theliterature procedure of Kagechika et al., J. Med. Chem. 1988, 31, 2182,incorporated herein by reference) is reacted with thionyl chloride,followed by ethyl 2-fluoro-4-amino-benzoate (Compound G) to yield ethyl2-fluoro-4-[(3′, 5′-di-tert-butylphenyl)carbamoyl]benzoate (Compound 5).As still another example, O-methoxymethyl-3,5-di-tert-butylsalicylicacid (Compound F) is reacted with ethyl 2-fluoro-4-amino-benzoate(Compound G) in the presence of 4-dimethylaminopyridine (DMAP) catalystand 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) togive ethyl2-fluoro-4-[(2′-methoxymethyl-3′,5′-di-tert-butylphenyl)carbamoyl]benzoate(Compound N). The methoxymethyl protecting group is removed fromCompound N by treatment with borontrifluoride ethereate and thiophenolto yield ethyl2-fluoro-4-[(2′-hydroxy-3′,5′-di-tert-butylphenyl)carbamoyl]benzoate(Compound 7).

[0089] In yet another example shown in Reaction Scheme 5,2,6-di-tert-butylisonicotinic acid (Compound C) is reacted with thionylchloride (SOCl₂), the resulting intermediate acid chloride is reactedwith methyl 2,6-difluoro-4-amino benzoate (Compound I), followed bysaponification of the ester group, to yield2,6-difluoro-4-[(2′,6′-di-tert-butylpyrid-4′yl)carbamoyl]benzoic acid(Compound 10). 3,5-Di-tert-butylbenzoic acid is subjected to the samesequence of reactions to provide2,6-difluoro-4-[(3′,5′-di-tert-butylphenyl)carbamoyl]benzoic acid(Compound 12).

[0090] As yet another example, shown in Reaction Scheme 5,2,6-di-tert-butylisonicotinic acid (Compound C) is reacted with thionylchloride (SOCl₂), followed by methyl 2-nitro-4-aminobenzoate (CompoundK) and saponification of the ester function to give2-nitro-4-[(2′,6′-di-tert-butylpyrid-4′-yl)carbamoyl]benzoic acid(Compound 14).

SPECIFIC EXAMPLES

[0091] 4-Bromomethyl-2,6-di-t-butylpyridine (Compound A)

[0092] To a mixture of 2,6-di-t-butyl-4-methylpyridine (Aldrich, 2.0 g,9.73 mmol) in 25 ml of dry CCl₄ was added benzoyl peroxide (24 mg, 0.097mmol) and NBS (1.9 g, 10.7 mmol). The reaction mixture was refluxed for16 hours. After it cooled to room temperature, the solvent was removedin vacuo and the residue was purified by column chromatography (silicagel, hexane) to give an oil (1.957 g) which contained 82% of the desiredproduct and 18% of the starting material. ¹H NMR δ7.09 (s, 2H), 4.39 (s,2H), 1.35 (s, 18H).

[0093] 4-Hydroxymethyl-2,6-di-t-butylpyridine (Compound B)

[0094] A heterogeneous solution of 4-bromomethyl-2,6-di-t-butylpyridine(Compound A, 1.743 g, 82% purity) in 20 ml of 12% NaOH in water and 10ml of 1,4-dioxane was refluxed for 12 hours. The solution spontaneouslyseparated into two layers as it cooled to room temperature. The upperlayer was separated and ethyl acetate was added. This organic layer wasthen washed with brine, water and dried over MgSO₄. The desired productwas purified by column chromatography (ethyl acetate/hexane 1/9) to givea white solid. ¹H NMR δ7.09 (s, 2H), 4.67 (d, J=4.4 Hz, 2H), 2.3 (b,1H), 1.36 (s, 18H).

[0095] 2,6-Di-t-butylisonicotinic Acid (Compound C)

[0096] Jone's reagent was added dropwise to a solution of4-hydroxymethyl-2,6-di-t-butylpyridine (Compound B, 302 mg, 1.37 mmol)in 5 ml of acetone until the solution changed color from light yellow toorange (55 drops of Jone's reagent were consumed). After 5 minutes 2 mlof isopropanol were added to the reaction mixture, and a greenprecipitate of Cr³⁺ salt was formed. The precipitate was removed byfiltration and the solution was diluted with ethyl acetate, then washedwith brine, water and dried over MgSO₄. After filtration, the solventwas removed to give the desired product as a white solid (227 mg). ¹HNMR δ7.71 (s, 2H), 1.34 (s, 18H).

[0097] 2-Bromo-4,6-di-t-butylphenol (Compound D)

[0098] To a solution of 2,4-di-t-butylphenol (Aldrich, 2.0 g, 9.7 mmol)in 2 ml of HOAc was added Br₂ (0.5 ml, 9.7 mmol). The reaction mixturewas stirred at room temperature for 12 hours. Solvent was removed underreduced pressure and the residue was purified by column chromatography(ethyl acetate/hexane 1/20) to yield the desired product (2.54 g) as awhite solid. ¹H NMR δ 7.33 (d, J=2.3 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H),1.41 (s, 9H), 1.29 (s, 9H).

[0099] O-Methoxymethyl-2-bromo-4,6-di-t-butylphenol (Compound E)

[0100] To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D 2.54 g,8.88 mmol) and catalytic amount of Bu₄NI in 20 ml of dry CH₂Cl₂ at 0° C.was added diisopropylethylamine (9.51 ml, 53 mmol), followed bymethoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture washeated to 45° C. for 12 hours. The reaction mixture was then washed with10% citric acid, then NaHCO₃ (sat.), brine, and dried over MgSO₄. Afterfiltration and removal of the solvent under reduced pressure, theresidue was purified by column chromatography (pure hexane) to yield thetitle compound (2.79 g) as a colorless oil. ¹H NMR δ7.40 (d, J=2.44 Hz,1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H),1.29 (s, 9H).

[0101] O-Methoxymethyl-3′,5′-di-t-butylsalicylic acid (Compound F)

[0102] To a solution of O-methoxymethyl-2-bromo-4,6-di-t-butylphenol(Compound E, 2.79 g, 8.5 mmol) in 30 ml of dry THF at −78° C. under Arwas added 11 ml of t-BuLi (1.7 M in hexane, 18.7 mmol). This mixture wasstirred at −78° C. for 1 hour. Then CO₂ (g) was bubbled into thesolution at −78° C. for 1 hour. After removal of the CO₂ stream, thereaction mixture was stirred for an additional hour at −78° C. Then 10%of HCl was added and the mixture was allowed to warm to room temperatureand extracted with ethyl acetate. The organic layer was washed withbrine and dried over Na₂SO₄. After concentration, the residue waspurified by column chromatography (ethyl acetate/hexane 1/1) to yieldthe title compound as a white solid (492 mg). ¹H NMR δ 7.75 (d, J=2.81Hz, 1H), 7.60 (d, J=2.8 Hz, 1H), 5.07 (s, 2H), 3.62 (s, 3H), 1.33 (s,9H), 1.26 (s, 9H).

[0103] Ethyl 4-Amino-2-fluorobenzoate (Compound G)

[0104] To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol,Aldrich) and Na₂Cr₂O₇ (2.74 g, 8.4 mmol) in 13.7 ml of HOAc was addedslowly 6.83 ml of H₂SO₄. This mixture was slowly heated to 90° C. for 1hour to give a greenish heterogeneous solution. The mixture was cooledto room temperature and diluted with ethyl acetate. The pH of thesolution was adjusted to 4 with aqueous NaOH. The mixture was extractedwith more ethyl acetate. The combined organic layers were washed withNaHCO₃ (sat.), then brine and dried over Na₂SO₄. After filtration, thesolution was concentrated to dryness which then was dissolved in 6 ml ofSOCl₂, and heated at 80° C. for 1 hour. The excess of SOCl₂was removedunder reduced pressure and the residue was dissolved in 5 ml of CH₂Cl₂,2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at roomtemperature for 2 hours and concentrated to dryness. Ethyl2-fluoro-4-nitrobenzoate was obtained as a white solid after columnchromatography of the residue with ethyl acetate/hexane (1/9). Thissolid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) wasadded. Hydrogenation converted ethyl 2-fluoro-4-nitrobenzoate into thetitle compound.

[0105]¹H NMR δ7.77 (t, J=8.4 Hz, 1H), 6.41 (dd, J₁=8.6, J₂=2.2 Hz, 1H),6.33 (dd, J₁=13.0, J₂=2.2 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 4.3 (b, 2H),1.37 (t, J=7.1 Hz, 3H).

[0106] Methyl 4-Amino-2.6-difluorobenzoate (Compound I)

[0107] A solution of trifluorobenzoic acid (150 mg, 0.85 mmol, Aldrich)in 0.5 ml of SOCl₂ was heated under reflux for 2 hours. The reactionmixture was cooled to room temperature, and excess of SOCl₂ was removedunder reduced pressure. The residue was dissolved in 1 ml of pyridineand 0.2 ml of methanol. After stirring at room temperature for 30 min,solvent was removed and the residue was purified by columnchromatography (ethyl acetate/hexane 1/10) to give methyltrifluorobenzoate as a colorless oil. This oil was then dissolved in 1ml of CH₃CN, then a solution of NaN₃ (100 mg, 1.54 mmol) in 0.5 ml ofwater was added. The reaction mixture was refluxed for two days. Saltwas removed by filtration and the remaining solution was concentrated toan oil. This oil was then dissolved in 1 ml of methanol, followed by acatalytic amount of Pd/C (10%, w/w). The reaction mixture washydrogenated for 12 hours. Catalyst was removed and the solution wasconcentrated to an oil. After column chromatography (ethylacetate/hexane 1/3), the title compound was obtained as colorlesscrystals.

[0108]¹H NMR δ6.17 (d, J=10.44 Hz, 2H), 4.2 (b, 2H), 3.87 (s, 3H).

[0109] Methyl 2-Nitro-4-aminobenzoate (Compound K)

[0110] 2-Nitro-4-aminobenzoic acid (261 mg, 1.43 mmol) was dissolved in1 ml of SOCl₂. The solution was refluxed for 1 hour. Excess SOCl₂ wasremoved under reduced pressure and 5 ml of CH₂Cl₂, 1 ml of MeOH and TEA(0.24 ml, 1.7 mmol) were added to the residue. The reaction mixture wasstirred at room temperature for 2 hours. Excess MeOH and TEA wereremoved and the residue was purified by column chromatography with ethylacetate/hexane (1/3) to yield the title compound as a yellow solid (316mg). ¹H NMR δ7.69 (d, J=8.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.67 (dd,J=8.3; 2.1 Hz, 1H), 4.31 (b, 2H), 3.94 (s, 3H).

[0111] Ethyl 2-fluoro-4-[(2′6′-di-t-butylpyrid-4′-l)carbamoyl]benzoate(Compound 1)

[0112] A solution of 2,6-di-t-butylisonicotinic acid (Compound C, 47.3mg, 0.20 mmol) in 2 ml of SOCl₂ was heated under reflux for 2 hours.Excess SOCl₂ was removed in vacuo and the residue was dissolved in 2 mlof dry CH₂Cl₂, and ethyl 2-fluoro-4-aminobenzoate (Compound G, 40.2 mg,0.22 mmol) and pyridine (0.0835 ml, 0.69 mmol) were added. The reactionmixture was stirred at room temperature for 12 hours. Solvent wasremoved and the residue was purified by column chromatography (ethylacetate/hexane 1/9) to yield the title compound (71.2 mg) as whitecrystals. ¹H NMR δ 8.56 (b, 1H), 7.91 (t, J=8.36 Hz, 1H), 7.53 (dd,J=12.82, 2.0 Hz, 1H), 7.39 (dd, J=8.7, 2.0 Hz, 1H), 4.33 (q, J=7.1 Hz,2H), 1.37 (t, J=7.1 Hz, 3H), 1.35 (s, 18H).

[0113] Ethyl 4-[(2′, 6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoate(Compound 3)

[0114] Using the same procedure as for the synthesis of ethyl2-fluoro-4-[(2′6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoate (Compound 1)but using 2,6-di-t-butylisonicotinic acid (Compound C, 101 mg, 0.43mmol) and ethyl 4-aminobenzoate (78 mg, 0.47 mmol), the title compoundwas obtained as a white solid (135 mg). ¹H NMR δ8.43 (b, 1H),, 8.02 (d,J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.48 (s, 2H), 4.33 (q, J=7.1 Hz,2H), 1.38 (t, J=7.1 Hz, 3H), 1.35 (s, 18H).

[0115] Ethyl 2-Fluoro-4-[(3′,5′-di-t-butylphenyl)carbamoyl]benzoate(Compound 5)

[0116] Using the same procedure as for the synthesis of ethyl2-fluoro-4-[(2′6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoate (Compound 1)but using 3,5-di-t-butylbenzoic acid (60 mg, 0.26 mmol, available byliterature procedure, see Kagechika et al. J. Med Chem. 1988 31,2182-2192) and ethyl 2-fluoro-4-aminobenzoate (Compound G, 51.5 mg, 0.28mmol), the title compound was obtained as a white solid (66 mg). ¹H NMRδ8.21 (b, 1H), 7.93 (t, J=8.3 Hz, 1H), 7.79 (dd, J=12.8, 2.0 Hz, 1H),7.67 (d, J=1.8 Hz, 2H), 7.65 (t, J=1.7 Hz, 1H), 7.35 (dd, J=8.7, 2.1 Hz,1H), 4.36 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H), 1.36 (s, 18H).

[0117] Ethyl2-Fluoro-4-[(2′-methoxymethyl-3′,5′-di-t-butylphenyl)carbamoyl]benzoate(Compound N)

[0118] To a mixture of O-methoxymethyl-3′,5′-di-t-butylsalicylic acid(Compound F, 150 mg, 0.51 mmol), 4-dimethylaminopyridine (142 mg, 0.61mmol) and ethyl 2-fluoro-4-aminobenzoate (Compound G, 102 mg, 0.56 mmol)in 5 ml of dry CH₂Cl₂ was added1-(3-di-methylaminopropyl)-3-ethylcarbodiimide hydrochloride (117 mg,0.61 mmol). The reaction mixture was stirred at room temperature for 12hours. Solvent was evaporated in vacuo and the residue was dissolved inethyl acetate, then washed with brine, water and dried over MgSO₄. Afterfiltration, solvent was removed and the residue was purified by columnchromatography (ethyl acetate/hexane 1/3) to give the title compound (58mg). ¹H NMR δ8.97 (b, 1H), 7.94 (t, J=8.37 Hz, 1H), 7.78 (d, J=2.7 Hz,1H), 7.61 (d, J=13.0 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.35 (d, J=8.7 Hz,1H), 5.00 (s, 2H), 3.53 (s, 3H), 4.38 (q, J=7.1 Hz, 2H), 1.47 (s, 9H),1.39 (t, J=7.2 Hz, 3H), 1.33 (s, 9H).

[0119] Ethyl 2-Fluoro-4-[(2′-hydroxy-3′,5′-di-t-butylphenylcarbamoyl]benzoate (Compound 7)

[0120] To a solution of ethyl2-fluoro-4-[(2′-methoxymethyl-3′,5′-di-t-butylphenyl)carbamoyl]benzoate(Compound N, 34 mg, 0.07 mmol) in 1 ml of THF were added 10 drops ofHOAc. The reaction mixture was heated to reflux for 12 hours. Solventwas removed and ethyl acetate was added. The solution was washed withNaCHO₃ (sat.), brine, water and dried over MgSO₄. Solvent was removed invacuo to give an oil. The oil was allowed to be exposed to theatmosphere for 12 hours during which time crystals formed. The crystalswere collected and washed several times with hexane to afford the titlecompound as a white solid (13.5 mg). ¹H NMR δ10.73 (s, 1H), 7.98 (d,J=2.56 Hz, 1H), 7.88 (b, 1H), 7.75 (t, J=8.26 Hz, 1H), 7.60 (d, J=2.44Hz, 1H), 7.32 (dd, J=12.3, 2.0 Hz, 1H), 7.02 (dd, J=8.6, 2.0 Hz, 1H),4.35 (q, J=7.2 Hz, 2H), 1.39 (s, 9H), 1.37 (t, J=7.2 Hz, 3H), 1.5 (s,9H).

[0121] 2,6-Difluoro-4-[(2′,6′-di-t-butylpyrid-4′yl)carbamoyl]benzoicAcid (Compound 10)

[0122] To 2,6-di-t-butylisonicotinic acid (Compound C, 20 mg, 0.085mmol) was added 1 ml of SOCl₂. The mixture was heated under reflux for 2hours. After cooling to room temperature, excess SOCl₂ was removed andthe residue was dissolved in 2 ml of CH₂Cl₂. To this solution was addedmethyl 2,6-difluoro-4-aminobenzoate (Compound I, 16 mg, 0.085 mmol) andtriethylamine (0.015 ml, 0.1 mmol). The reaction mixture was kept atroom temperature for 2 hours and then concentrated to dryness. Theresidue was purified by column chromatography with ethyl acetate/hexane(1/10) to yield the methyl ester of the title compound. This wassaponified according to the general procedure (see below) to give thetitle compound as a colorless solid. ¹H NMR δ7.44 (s, 2H), 7.40 (d,J=11.8 Hz, 2H) 1.37 (S, 18H).

[0123] 2,6-Difluoro-4-[(3′,5′-di-t-butylphenyl)carbamoyl]benzoic Acid(Compound 12)

[0124] Using the same procedure as for the preparation of2,6-difluoro-4-[(2′,6′-di-t-butylpyrid-4′yl)carbamoyl]benzoic acid(Compound 10) but using 3,5-di-t-butylbenzoic acid (37 mg, 0.16 mmol)and methyl 2,6-difluoro-4-aminobenzoate (Compound I, 29 mg, 0.16 mmol),the title compound was obtained as colorless crystals. ¹H NMR δ7.92 (b,1H) 7.60 (m, 3H), 7.42 (d, J=10.0 Hz, 2H), 1.38 (s, 18H).

[0125] 2-Nitro-4-[(2′,6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoic Acid(Compound 14)

[0126] Using the same procedure as for the preparation of2,6-difluoro-4-[(2′,6′-di-t-butylpyrid-4′yl)carbamoyl]benzoic acid(Compound 10) but using 2,6-di-t-butylisonicotinic acid (40 mg, 0.17mmol) and methyl 2-nitro-4-aminobenzoate (Compound K, 33 mg, 0.17 mmol),the title compound was obtained as a light yellow oil. ¹H NMR δ(acetone-d⁶) 10.25 (b, 1H), 8.32 (s, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.93(b, 1H), 7.70 (s, 2H), 1.36 (s, 18H).

[0127] General Procedure for the Syntheses of Benzoic Acid Derivativesby Hydrolyzing the Corresponding Methyl or Ethyl Esters

[0128] To a solution of ester (3.0 mmol) in 20 ml of EtOH was added 5 mlof 1 N NaOH in water. The reaction mixture was stirred at roomtemperature for overnight and neutralized with 10% HCl to PH=5. Thealcohol was removed by evaporation and the aqueous layer was extractedwith ethyl acetate (3×10 ml). The ethyl acetate layer was further washedwith NaHCO₃ (sat.), brine and dried over MgSO₄. After concentration, thedesired carboxylic acid was obtained which could be recrystallized inethyl acetate or acetonitrile.

[0129] 2-Fluoro-4-[(2′,6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoic Acid(Compound 2)

[0130]¹H NMR δ (CD₃OD) 7.92 (t, J=8.36 Hz, 1H), 7.82 (dd, J=12.82, 2.0Hz, 1H), 7.63 (s, 2H), 7.55 (dd, J=8.7, 2.1 Hz, 1H), 1.39 (s, 18H).

[0131] 4-[(2′,6′-Di-t-butylpyrid-4′-yl)carbamoyl]benzoic acid (Compound4)

[0132]¹H NMR δ (CD₃OD) 8.02 (d, J=8.85 Hz, 2H), 7.85 (d, J=8.85 Hz, 2H),7.63 (s, 2H), 1.40 (s, 18H).

[0133] 2-Fluoro-4-[(3′,5′-di-t-butyl)phenylcarbamoyl]benzoic Acid(Compound 6)

[0134]¹H NMR δ (CD₃OD) 7.92 (t, J=8.3 Hz, 1H), 7.80 (dd, J=12.8, 2.0 Hz,1H), 7.79 (d, J=1.8 Hz, 2H), 7.69 (t, J=1.7 Hz, 1H), 7.57 (dd, J=8.7,2.1 Hz, 1H), 1.37 (s, 18H).

[0135] 2-Fluoro-4- [(2′-hydroxy-3′,5′-di-t-butyl)phenylcarbamoyl]benzoicAcid (Compound 8)

[0136]¹H NMR δ (acetone-d₆) 12.3 (b, 1H), 10.07 (b, 1H), 7.98 (t, J=8.48Hz, 1H), 7.80 (m, 2H), 7.58 (d, J=2.3 Hz, 1H), 7.56 (dd, J=8.8, 2.0 Hz,1H), 1.44 (s, 9H), 1.31 (s, 9H).

What is claimed is:
 1. A compound of the formula

wherein X is CH or N; R₁ is independently H or alkyl of 1 to 6 carbons;m is an integer having the value of 0-5; p is an integer having thevalue of 0-2; r is an integer having the value 0-2; L is —(C═Z)—NH— or—NH—(C═Z)— where Z is O or S; Y is a phenyl or naphthyl group, orheteroaryl selected from a group consisting of pyridyl, thienyl, furyl,pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl andpyrrazolyl, said phenyl, naphthyl and heteroaryl groups being optionallysubstituted with one or two R₁ groups; W is a substituent selected fromthe group consisting of F, Br, Cl, I, C₁₋₆alkyl, fluoro substituted C₁₋₆alkyl, NO₂, N₃, OH, OCH₂OCH₃, OC₁₋₁₀alkyl, tetrazol, CN, SO₂C₁₋₆-alkyl,SO₂C₁₋₆-alkyl, SO₂C₁₋₆-fluoro substituted alkyl, SO—C₁₋₆ alkyl,CO—C₁₋₆alkyl, COOR₈, phenyl, phenyl itself substituted with a W groupother than with phenyl or substituted phenyl with the proviso that whenX is CH and r is 0 then p is not 0 and at least one W group is notalkyl; A is (CH₂)_(q) where q is 0-5, lower branched chain alkyl having3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbonsand 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triplebonds, and B is COOH or a pharmaceutically acceptable salt thereof,COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁, CHO, CH(OR₁₂)₂, CHOR₁₃O,—COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, where R₇ is an alkyl, cycloalkyl or alkenylgroup containing 1 to 5 carbons, R₈ is an alkyl group of 1 to 10 carbonsor trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R₈ is phenyl or loweralkylphenyl, R₉ and R₁₀ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R₁₁ is lower alkyl, phenyl or lower alkylphenyl, R₁₂ islower alkyl, and R₁₃ is divalent alkyl radical of 2-5 carbons.
 2. Acompound in accordance with claim 1 wherein L is —(C═Z)—NH—.
 3. Acompound in accordance with claim 1 wherein L is —NH—(C═Z)—.
 4. Acompound in accordance with claim 1 wherein X is CH.
 5. A compound inaccordance with claim 1 wherein X is N.
 6. A compound in accordance withclaim 1 wherein Y is selected from the group consisting of phenyl,pyridyl, 2-thiazolyl, thienyl and furyl.
 7. A compound in accordancewith claim 6 wherein Y is phenyl.
 8. A compound in accordance with claim1 wherein W is branch-chained alkyl, F, NO₂, Br, I, CF₃, N₃, or OH.
 9. Acompound in accordance with claim 8 wherein (W)_(p) represents twobranch-chained alkyl groups.
 10. A compound in accordance with claim 8wherein (W)_(r) represents one or two fluoro or one or two NO₂ groups.11. A compound of the formula

wherein X is CH or N; R₁ is independently H or alkyl of 1 to 6 carbons;m is an integer having the value of 0-5; p is an integer having thevalue of 0-2; r is an integer having the value 0-2; Z is O or S; W is asubstituent selected from the group consisting of F, Br, Cl, I,C₁₋₆alkyl, fluoro substituted C₁₋₆ alkyl, NO₂, N₃, OH, OCH₂OCH₃,OC₁₋₁₀alkyl, tetrazol, CN, SO₂C₁₋₆-alkyl, SO₂C₁₋₆-alkyl, SO₂C₁₋₆-fluorosubstituted alkyl, SO—C₁₋₆ alkyl, CO—C₁₋₆alkyl, COOR₈, phenyl, phenylitself substituted with a W group other than with phenyl or substitutedphenyl with the proviso that when X is CH and r is 0 then p is not 0 andat least one W group is not alkyl; A is (CH₂)_(q) where q is 0-5, lowerbranched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons,alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6carbons and 1 or 2 triple bonds, and B is COOH or a pharmaceuticallyacceptable salt thereof, COOR₈, CONR₉R₁₀, —CH₂OH, CH₂OR₁₁, CH₂OCOR₁₁,CHO, CH(OR₁₂)₂, CHOR₁₃O, —COR₇, CR₇(OR₁₂)₂, CR₇OR₁₃O, where R₇ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R₈ is analkyl group of 1 to 10 carbons or trimethylsilylalkyl where the alkylgroup has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, orR₈ is phenyl or lower alkylphenyl, R₉ and R₁₀ independently arehydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of5-10 carbons, or phenyl or lower alkylphenyl, R₁₁ is lower alkyl, phenylor lower alkylphenyl, R₁₂ is lower alkyl, and R₁₃ is divalent alkylradical of 2-5 carbons.
 12. A compound in accordance with claim 11wherein X is CH.
 13. A compound in accordance with claim 12 wherein Z is0.
 14. A compound in accordance with claim 13 wherein A is (CH₂)_(q),and B is COOH or a pharmaceutically acceptable salt thereof, COOR₈ orCONR₉R₁₀.
 15. A compound in accordance with claim 14 wherein (W)_(p)represents two branch-chained alkyl groups and (W)_(r) represents one ortwo fluoro or one or two NO₂ groups.
 16. A compound in accordance withclaim 15 wherein the phenyl ring is 1,4-substituted by the (C═Z)NH— and—A—B— groups.
 17. A compound of the formula

wherein X is CH or N; W₁ is H or OH; W₂ is H, F or NO₂; W₃ is H, F orNO₂; R₈ is H, CH₃ or C₂H₅, with the proviso that when X is CH then W₁,W₂ and W₃ all are not H.
 18. A compound in accordance with claim 17wherein X is N.
 19. A compound in accordance with claim 18 wherein W₂ isF and W₃ is H.
 20. A compound in accordance with claim 19 which is:ethyl 2-fluoro-4-[(2′,6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoate, or2-fluoro-4-[(2′,6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoic acid.
 21. Acompound in accordance with claim 18 where in W₂ is F and W₃ is F.
 22. Acompound in accordance with claim 21 which is: methyl2,6-difluoro-4-[(2′,6′-di-t-butylpyrid-4′yl)carbamoyl]benzoate, or2,6-difluoro-4-[(2′,6′-di-t-butylpyrid-4′yl)carbamoyl]benzoic acid. 23.A compound in accordance with claim 18 wherein W₂ is NO₂.
 24. A compoundin accordance with claim 23 which is: methyl2-nitro-4-[(2′,6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoate, or2-nitro-4-[(2′,6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoic acid.
 25. Acompound in accordance with claim 18 wherein W₁, W₂ and W₃ are allhydrogen.
 26. A compound in accordance with claim 25 which is: ethyl4-[(2′,6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoate, or4-[(2′,6′-di-t-butylpyrid-4′-yl)carbamoyl]benzoic acid.
 27. A compoundin accordance with claim 17 wherein X is CH.
 28. A compound inaccordance with claim 27 wherein W₂ is F and W₃ is H.
 29. A compound inaccordance with claim 28 which is: ethyl2-fluoro-4-[(3′,5′-di-t-butylphenyl)carbamoyl]benzoate, or2-fluoro-4-[(3′,5′-di-t-butyl)phenylcarbamoyl]benzoic acid.
 30. Acompound in accordance with claim 27 wherein W₂ is F and W₃ is F.
 31. Acompound in accordance with claim 30 which is: methyl2,6-difluoro-4-[(3′,5′-di-t-butylphenyl)carbamoyl]benzoate, or2,6-difluoro-4-[(3′,5′-di-t-butylphenyl)carbamoyl]benzoic acid.
 32. Acompound in accordance with claim 27 wherein w is OH.
 33. A compound inaccordance with claim 32 which is: ethyl2-fluoro-4-[(2′-hydroxy-3′,5′-di-t-butylphenyl)carbamoyl]benzoate, or2-lfuoro-4-[(2′-hydroxy-3′,5′-di-t-butyl)phenyl-carbamoyl]benzoic acid.